Oripavine derivatives and their uses as medicines

ABSTRACT

The present invention relates to oripavine derivatives of formula (I),  
                 
         wherein R 1  is hydrogen or methyl, R 2  is methyl, cyclopropyl methyl, cyclobutyl methyl or allyl, R 3  is thiophenyl ethyl or cycloalkyl methyl where the cycloalkyl has 3 to 6 carbon atoms, or nontoxic pharmaceutically acceptable salts thereof. These compounds can be used for the preparation of analgesics or abstinence agents of opium habit-forming drugs.

FIELD OF THE INVENTION

The present invention relates to novel oripavine derivatives, theirnon-toxic pharmaceutically acceptable salts, and their uses in thepreparation of analgesics or abstinence agents of opium habit-formingdrugs.

BACKGROUND ART

The Great Britain patent 1136214 disclosed compounds represented by thefollowing formula:

wherein R¹ is hydrogen or methyl, R² is cyclopropyl methyl or allyl, R³is alkyl, phenyl or phenyl alkyl. These compounds have potent centralanalgesic activity and opiate antagonist activity.

Among them, buprenorphine (where R¹ is hydrogen, R² is cyclopropylmethyl, R³ is tert-butyl) has good analgesic activity and littledependence with potency 25-30 times as that of morphine and lessdependence. It has now been widely used as analgesics andanti-addiction. But buprenorphine only have moderate efficacy (40% thatof morphine) and low bioavailability. So it could not be administeredorally.

Buprenorphine

U.S. Pat. No. 3,931,189 disclosed buprenorphine analogues wherein R² isaromatic heterocyclic alkyl; Chinese patent CN1168377A disclosedbuprenorphine analogues wherein R³ is cyclobutyl or cyclopropyl.

Although the prior arts have given these teachings, it is still of greatneed for new drugs for the treatment of pain and addiction.

DETAILED DESCRIPTION OF THE INVENTION

The inventor of the present invention has discovered that the oripavinederivatives represented by the formula (X) or their pharmaceuticallyacceptable salts not only have strong analgesic potency and analgesicefficacy, but also exhibit good oral bioavailability, long acting time,low small animal body dependency. As a result, the invention has beencompleted.

Therefore, the present invention at one aspect aims to provide noveloripavine derivatives represented by the formula (I) and their non-toxicpharmaceutically acceptable salts.

The present invention at another aspect relates to a pharmaceuticalcomposition comprising as active ingredient oripavine derivativesrepresented by the formula (I) and their non-toxic pharmaceuticallyacceptable salts and pharmaceutically acceptable carriers.

The present invention relates to oripavine derivatives represented bythe ALSO formula (I):

wherein R¹ is hydrogen or methyl, R² is methyl, cyclopropyl methyl,cyclobutyl methyl or allyl, R³ is thiophenylethyl or cycloalkyl methylwhere the cycloalkyl has 3 to 6 carbon atoms, and their non-toxicpharmaceutically acceptable salts.

The compounds of the formula I are preferably selected from thecompounds represented by the following formulae:

or their non-toxic pharmaceutically acceptable salts.

The oripavine derivatives according to the present invention can beprepared by the following reaction schemes:

Starting material thebaine (II) is reacted with methyl vinyl ketone byDiels-Alder reaction to obtain a compound of formula III with a yield of80-90%; the resulting compound of formula III is hydrogenated in thepresence of palladium catalyst to obtain a compound of formula IV, theresulting compound of formula IV is reacted thiophenylethyl bromide byGrignard addition reaction to obtain a compound of formula V; thecompound of formula V is reacted with cyanobromide to give the compoundof formula VI substituted by N-cyano group, the compound of formula VIis hydrolyzed with potassium hydroxide to obtain a compound of formulaVII, which is a key intermediate. Finally the compound of formula VII issubjected alkylation reaction on nitrogen atom to yield the targetcompound.

The compounds of the invention wherein R³ is cycloalkyl methyl where thecycloalkyl has 3 to 6 carbon atoms can be prepared by the followingschemes:

the intermediate of formula VI obtained according to the first scheme isreacted with cyanobromide to obtain a compound of formula V′ substitutedby N-cyano group, the resulting compound of formula V′ is hydrolyzedwith potassium hydroxide to obtain a compound of VI′; the resultingcompound of formula VI′ is reacted with cyclopropyl methyl bromide toobtain an intermediate of formula VII′; the intermediate of formula VII′is subjected to Grignard addition reaction and then demethoxylated toyield target compound of formula I.

When a compound has sufficient acidic strength or basic capability toform a stable a nontoxic acidic or basic salt, it is appropriate thatthe compound is administered in the form of a salt. Examples ofpharmaceutically acceptable salts are organic addition salts formed withacids, these acids form physiologically acceptable anions, such astosylates, methyl sulfonates, acetates, citrates, malonates, tartrates,succinates, benzoates, ascorbates, alpjha-keto-glutaric acid salts,maleates, fumarates, benzenesulfonates, and alpha-glycerin phosphates.These acids also form suitable inorganic salts, including hydrobromides,hydrochlorides, sulfates, nitrates, bicarbonates and carbonates.

The pharmaceutically acceptable salts can be obtained by common methodsin the art, for example, a physiologically acceptable anion can beformed by reacting a compound with sufficient basic strength such as anamine with a suitable acid.

The compounds according to the invention can be administered in the formof pharmaceutical compositions comprising the compounds and appropriatecarriers. These pharmaceutical compositions can be prepared by variousprocesses and contain common carriers in the art. The guidelines forthese processes and components have been taught in Remington'sPharmaceutical Sciences, edited by E. W. Martin (Mark Publ. Co., 15^(th)Ed., 1975). For the necessity for the completeness of the invention, thereference document is introduced for reference. The compounds and thepharmaceutical compositions according to the invention can beadministered non-enterogastrically (such as intravenously,intraperitoneally, intramuscularly), locally, transdermally, orally orrectally.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is comparative curve of administering compound I₁ orally or bysubcutaneous injection.

MODE OF CARRYING OUT THE INVENTION

Following examples further describes the present invention, but notlimit the invention at any way.

EXAMPLE 1 Preparation of 7α-acetyl-6,14-endoetheno Tetrahydro Thebaine(III)

49.8 g of thebaine (It) and 140 ml of methyl vinyl ketone were heatedand refluxed for 1 hour. Excess methyl vinyl ketone was removed bydistillation under reduced pressure. To the residue was added 60 ml ofmethanol and the mixture was heated to dissolve the residue. Theresulting solution was cooled, the precipitated solid was filtered, andwashed with cooled methanol and dried to give 56.3 g of a compound offormula III with a melting point of 118-120° C., the yield is 89%.

EXAMPLE 2 Preparation of 7α-acetyl-6,14-endoethano Tetrahydro Thebaine(IV)

The mixture of 19.2 g of the compound of formula III, 4 g of 10% Pd—Cand 200 ml of absolute ethanol were hydrogenated at 50-60° C., 40-50Kg/cm⁻¹ of hydrogen pressure for 8-12 hours. Upon the completion of thereaction, the catalyst was filtered off and the filtrate wasconcentrated and cooled. The precipitated solid was filtered, and washedwith cooled ethanol and dried to give 15.4 g of a compound of formula IVwith a melting point of 135-137° C., the yield is 80%.

EXAMPLE 3 Preparation of7α-[(S)-J-hydroxy-1-methyl-3-(2-thiophenyl)-propyl]-6,14-endoethanoTetrahydro Thebaine (V)

The Grignard reagent was prepared by the reaction of 6.38 g (0.03 mol)of 2-thiophen-2-yl ethyl bromide and 4.9 g (0.2 mol) of magnesium in 100ml of ether. To the Grignard reagent solution was added drop-wise asolution of 4.9 g (0.013 mol) IV in 100 ml of dried benzene. The mixturewas heated and refluxed for 3 hours. Then the mixture was cooled to roomtemperature, and saturated ammonium chloride solution was added,extracted with ether, washed with water and then dried over MgSO₄. Thesolvent was removed under reduced pressure. The residue wasrecrystallized with methanol to give 4.54 g of a compound of formula Vwith a melting point of 183-185° C., the yield is 62%. By elementalanalysis, C₂₉H₃₇NO₄S has a theoretic value (%): C 70.30, H 7.47, N 2.83,experimental value (%) was C 70.18; H 7.56; N 2.74.

EXAMPLE 4 Preparation of N-cyano-7α-acetyl-6,14-endoethanoTetrahydro-nor-thebaine (V′)

1.6 g of cyanobromide was dissolved in 50 ml of chloroform, to thesolution was added 5 g of the compound of formula IV, after refluxingfor 12 hours, the solvent was removed under reduced pressure, theresidue was recrystallized with absolute ethanol to give 3.2 g of acompound of formula V′ with a melting point of 198-200° C., the yield is62.3%.

EXAMPLE 5 Preparation ofN-cyano-7α-[(S)-1-hydroxy-1-methyl-3-(thiophen-2-yl)-propyl]-6,14-endoethanoTetrahydro-nor-thebaine (VI)

4.07 g (0.0385 mol) of cyanobromide was dissolved in 18 ml of drymethylene chloride; to the refluxing solution was added 4.54 g(0.0092mol) of V in 18 ml of methylene chloride, after 4 hours of reaction, thesolvent was removed by distillation. The residue was recrystallized withabsolute ethanol to give 4.23 g of a compound of formula VI with amelting point of 171-173° C., the yield is 91.1%. By elemental analysis,C₂₉1H₃₄N₂O₄S has theoretic value (%): C, 68.77; H, 6.72; N, 5.53, andexperimental value (%) was: C 68.81, H 6.72, N 5.40.

EXAMPLE 6 Preparation of 7α-acetyl-6,14-endoethano TetrahydroTor-thebaine (VI′)

To 45 ml of 2 N hydrochloric acid was added 3.82 g of the compound offormula V′, the mixture was refluxed for 2 hours and then cooled to 0°C.; to the cooled solution was added dropwise 0.78 g of sodium nitrite.The reaction was continued until there was no gas released, the reactionmixture was neutralized with ammonia to pH8-9 and extracted withchloroform, dried with MgSO₄. The solvent was removed under reducedpressure and the residue was recrystallized with methanol to obtain 1.46g of a compound of formula VI′ with a melting point of >300° C., theyield is 40.8%.

EXAMPLE 7 Preparation of7α-[(S)-1-hydroxy-1-methyl-3-(2-thiophenyl)-propyl]-6,14-endoethanotetrahydro-nor-oripavine Hydrochloride (VII)

To 4 g of the compound of formula VI was added 50 ml of diethyleneglycol and 10 g of KOH. The mixture was stirred under N₂ at 190-200° C.for 1 hour. After finishing the reaction, the reaction mixture waspoured into ice-water, and saturated ammonium chloride solution wereadded to adjust the pH 8-9, The produced solid precipitate was collectedand recrystallized with methanol to yield 2.9 g of a compound of formulaVII with a melting point of 268-270° C., the yield is 72%. By elementalanalysis, C₂₇N₃₃NO₄S.HCl.H₂O has a theoretic value (%) C 62.18; H 6.91;N 2.69; an experimental value (%) C 62.30; H 6.87; N 2.38.

EXAMPLE 8 Preparation of N-cyclopropyl-7α-acetyl-6,14-endoethanoTetrahydro nor-thebaine (VII′)

To 275 ml of DMF was added 11.82 g of the compound of formula VI′, 5.43ml of cyclopropyl methyl bromide and 6.4 g of sodium hydrocarbonate. Themixture was heated stirring under N₂ at 70° C. for 16 hours. The solidwas filtered off, the filtrated was removed under reduced pressure, theresidue was extracted with methylene chloride, dried with MgSO₄. Thesolvent was removed under reduced pressure. The residue wasrecrystallized with methanol to give 8.2 g of a compound of formula VII′with a melting point of 104-106° C., the yield is 60.74%.

EXAMPLE 9 Preparation ofN-cyclopropyl-7α-[(S)-1-hydroxy-1-methyl-2-cyclopropyl-ethyl]-6,14-endoethanoTetrahydro-nor-thebaine (VIII)

The Grignard reagent was prepared by the reaction of 1.2 g ofcyclopropyl methyl bromide and 0.6 g of magnesium in 20 ml of ether. Tothe Grignard reagent solution was added drop-wise a solution of 0.88 gof the compound of formula VII′ in 30 ml of dried ether. The mixture washeated and refluxed for 4 hours. Then the mixture was cooled to roomtemperature, and saturated ammonium chloride solution was added, theorganic part was separated and the water part was extracted with ether 2times, the organic solution was combined and dried with Na₂SO₄. Thesolvent was removed under reduced pressure and the residue waschromatographed on a silica gel column, the product obtained translatedto hydrochloride with HCl-ether to give 0.55 g of a compound of formulaVIII which was used for the next step without further purification.

EXAMPLE 10 Preparation ofN-cyclopropylmethyl-7α-[(S)-1-hydroxy-1-methyl-3-(2-thiophenyl)-propyl]-6,14-endoethanoTetrahydro-nororipavine Hydrochloride (I₁)

To 210 ml of DMF was added 7 g (0.015 mol) of the compound of formulaVII, 4.1 g (0.03 mol) of cyclopropyl methyl bromide, 3.95 g (0.047 mol)of sodium hydro carbonate. The mixture was heated stirring under N₂ at70° C. for 16 hours. The solid was filtered off, the solvent of thefiltrate was removed under reduced pressure, the residue was extractedwith methylene chloride, dried with MgSO₄. The solvent was removed underreduced pressure. The residue was chromatographed on a silica gelcolumn, recrystallized with methanol to give 3.79 g of the compound I₁in the form of base in 48.4% yield, MP170-172° C. Take 1.4 g of theproduct and dissolved with absolute ethanol, to the solution was addeddropwise the ether solution of hydrochloride. The precipitated solid wascollected and recrystallized with absolute ethanol to give 1.21 g of thecompound I₁, melting pointing of 255-257° C. By elemental analysis,C₃₁₁H₃₈NO₄S.2HCl.0.5 H₂O has theoretic values (%): C 65.61 H 7.17 N 2.47S 5.64, and an experimental value (%) of 65.53 H 7.18 N 2.07 S 5.41. IR:3406 cm⁻¹ (w), v_(as) C₁₉—OH; 3224 cm⁻¹ (w), V_(as) C₃—OH 2989, 2926cm⁻¹ (m) γ, C_(1,2)—H,; 1634, 1609 cm⁻¹ (w),δ, ph-H, thiophenyl; 1080,1023 cm⁻¹ (s), δ, C—N, C—O; 1023 cm⁻¹ (s), δ, cyclopropyl methyl; ¹HNMR:δ(ppm, CDCl₄): 7.12-6.90 (dd, 2H,Ar—H); 6.85-6.50 (ddd, 3H, thiophenyl;5.17 (s, 1H, 3-OH); 3.56 (s, 1H, 5β-H); 3.55 (s, 3H, 6-OCH3); 3.00-1.61(m,15H, C_(20,21,15,16,9,10), C_(1′,2′), C₁₉—OH); 1.40 (m,3H,19-CH₃);1.10-0.09 (m, 11H,C_(17,18,7,8), C_(3′,4′)); ¹³CNMR: δ (ppm,CDCl₄): 119.471 (1C, C₁); 116.511 (1C, C₂); 117.352 (1C, C₃); 145.547(1C, C₄); 97.370 (1C, C₅); 80.506 (1C, C₆); 47.188 (1C, C₇); 31.599 (1C,C₈); 58.254 (1C, C₉); 43.636 (1C, C₁₀); 123.944 (1C, C₁₁); 132.211 (1C,C₁₂); 45.686 (1C, C₁₃); 35.880 (1C, C₁₄); 35.607 (1C, C₁₁); 75.771 (1C,C₁₆); 17.726 (1C, C₁₇); 29.763 (1C, C₁₈); 75.771 (1C, C₁₉); 43.454 (1C,C₂₀); 23.494 (1C, C₂₁); 23.236 (1C, C₁₉—CH₃); 52.759 (1C, C₆—OCH₃);146.004 (1C, C₂₂); 122.734 (1C, C₂₃); 128.047 (1C, C₂₄); 126.666 (C,C₂₅); 59.787 (1C, C_(1′)); 9.393 (1C, C_(2′)); 3.974, 3.484 (2C,C_(3′,4′))

EXAMPLE 11 Preparation ofN-cyclobutyl-methyl-7α-[(S)-1-hydroxy-1-methyl-3-(2-thiophenyl)-propyl]-6,14-endoethanoTetrahydro-nororipavine Hydrochloride (I₂)

To 25 ml of DMF was added 1 g (0.002 mol) of the compound of formulaVII, 0.64 g (0.0043 mol) of cyclobutyl methyl bromide, 0.53 g of sodiumhydrocarbonate, and 0.1 g of NaI. The mixture was heated stirring underN₂ at 70° C. for 16 hours. The solid was filtered off, the solvent ofthe filtrate was removed under reduced pressure, the residue wasextracted with methylene chloride, dried with MgSO₄. The solvent wasremoved under reduced pressure. The residue was chromatographed on asilica gel column. The product collected was dissolved with absoluteethanol, to the solution was added dropwise the ether solution ofhydrochloride. The precipitated solid was collected and recrystallizedwith methanol to give 0.59 g of 12 in 50.4% yield, MP 241-3° C. Byelemental analysis, C₃₂H₄₀NO₄S.HCl.1.5H₂O has a theoretic value (%): C64.27H 7.36 N 2.34 S 5.35, experimental value (%): C 65.10H 7.41 N 2.06S 5.01.

EXAMPLE 12 Preparation ofN-allyl-methyl-7α-[(S)-1-hydroxy-1-methyl-3-(2-thiophenyl)propyl]-6,14-endoethano Tetrahydro-nor-oripavine Hydrochloride (I₃)

To 205 ml of DMF was added 1.5 g (0.003 mol) of the compound of formulaVII, 0.60 g (0.004 mol) of allyl bromide and 0.53 g of sodiumhydrocarbonate. The mixture was heated stirring under N₂ at 70° C. for16 hours. The solid was filtered off, the solvent of the filtrate wasremoved under reduced pressure, the residue was extracted with methylenechloride; dried With MgSO₄. The solvent was removed under reducedpressure. The residue was chromatographed on a silica gel column. Theproduct collected was dissolved with absolute ethanol, to the solutionwas added dropwise the ether solution of hydrocloride. The precipitatedsolid was collected and recrystallized with methanol to give 0.35 g ofthe compound of 13 with a melting point of 228-30° C., the yield is 22%.By elemental analysis, C₃₀H₃₆NO₄S.HCl has theoretic value (%): C 66.23H7.00 N 2.58 S 5.89; experimental value (%) C 66.40 H 7.14 N 2.36 S 5.80.

EXAMPLE 13 Preparation of7α-[(S)-1-hydroxy-1-methyl-3-(2-thiophenyl)-propyl]-6,14-endoethanotetrahydro-oripavine hydrochloride (I₄)

To 50 ml of diethylene glycol was added 4 g of the compound of formula Vand 10 g of KOH. The mixture was stirred under N₂ at 190-200° C. for 1hour and then was poured into ice-water. Saturated ammonium chloridesolution were added to adjust pH 8-9. The precipitated solid wascollected and recrystallized with methanol give 2.9 g of base of 14 in72 yield, MP 268-270° C. The base was translated to salt ofhydrochloride with HCl-ether to give 3.1 g of a compound of formula I₄with a melting point of >300° C. By element analysis, C₂₈H₃₄NQ₄S.HCl hastheoretic value (%) C 64.86 H 6.95 N 2.70 S 6.18; experimental value(%): C 64.42H 7.22 N t 2.54 S 5.20.

EXAMPLE 14 Preparation ofN-cyclopropylmethyl-7α-[(S)-1-hydroxy-1-methyl-2-cyclopropyl-ethyl]-6,14-endoethanoTetrahydro-nor-oripavine Hydrochloride (I₅)

To 8 ml of diethylene glycol was added 1.8 g of KOH. The mixture washeated under N₂ at 205-6° C. until the temprature stable. Then 0.55 g ofthe compound of formula VIII was added to the reaction mixture, stirredat the same temperature for 2 hours. The reaction mixture was pouredinto ice-water. Saturated ammonium chloride solution was added to adjustpH 8-9. The precipitated solid was collected and chromatographed onsilica gel column. The product collected and made to salt ofhydrochloride with HCl-ether, 0.16 g of a compound I₅ was obtained in30% yield, melting pointing of 185-190° C. By element analysis,C₂₉H₄₀NO₄. HCl has theroretic value (%): C, 69.25; H, 7.96; N, 2.79, S6.37; experimental value (%); C, 69.24; H, 7.72; N, 2.45, S 6.68.

According to similar methods to prepare the compound I₅,N-cyclopropylmethyl-7α-[(S)-1-hydroxy-1-methyl-2-cyclopentyl-ethyl]-6,14-endoethanotetrahydro-nor-oripavine hydrochloride (I 6), with a melting point of270° C., decomposed, was prepared by reaction of cyclopropyl methylchloride compound via Grinard addition reaction. AlsoN-cyclopropylmethyl-7α-[(S)-1-hydroxy-1-methyl-cyclohexyl-ethyl]-6,14-endoethanotetrahydro-nor-oripavine hydrochloride (I 7), with a melting point of241-6° C., decomposed, was prepared by reaction of cyclohexyl methylchloride compound.

Experiment of Pharmacological Activity Evaluation

Pharmacological effect of the compounds according to the invention wasmeasured by the methods of acetic acid writhing test, 55° C. hot platetest, rat 55° C. hot water bath test and so on.

1. Antinociceptive Tests

1.1. Methods

(1) Mice 55° C. Hot plate Test (sc/po)

Female mice weighing 18-22 g were used in the test. The latency wasmeasured as the period from placing the animals on the 55° C. plate tothe appearance of response to the hot nociceptive stimulus (lickinghindpaws, jump ing and flicking of paw s) before and afteradministration of drugs (sc/po), respectively. Each group had 8 mice.The cut off time was 60 sec. The results were expressed as possiblemaximal analgesic percentage (PMAP),${PMAP} = {\frac{{{{Latency}\quad{after}\quad{ad}\quad{ministration}} - {{Latency}\quad{before}\quad{ad}\quad{ministration}}}\quad}{60 - {{Latency}\quad{before}\quad{admin}\quad{istration}}} \times 100}$

-   -   ED₅₀ was calculated with Logit program.        (2) Rat Hot Water Bath Test

Male and female (1:1) Wistar rats weighing 180-200 g were used. Thelatency was defined as a period from insertion of the tip part of therat tail into 55° C. hot water to withdrawal of tail from it before andafter administration of drugs, respectively. Each group had 8 mice. Theresults were expressed as PMAP and the computational method was same asthat as mentioned above. The longest latency was defined as 15 s. Andthen ED₅₀ was calculated with Logit program.

(3) Acetic Acid Writhing Test

Male and female (1:1) mice weighing 18-22 g were used. Acetic acid(0.6%, 0.4 ml per mouse, ip) was administered to each animal. 5 minlater, the frequency of writhing in the following 15 min was counted.The drugs or normal saline were administrated by sc 30 min and by po 60min prior to injection of acetic acid, respectively. ED₅₀ was calculatedwith Logit program,${{analgesic}\quad{percentage}} = {\frac{{{writhing}\quad{number}\quad{in}\quad{normal}\quad{saline}} - {{writhing}\quad{number}\quad{in}\quad{drug}}}{{writhing}\quad{number}\quad{in}\quad{normal}\quad{saline}} \times 100}$TABLE 1 Antinociceptive activity of compounds acetic acid writhing testhot plate test ED₅₀ Max. ED₅₀ Compounds (μg · kg⁻¹) efficacy (%) (μg ·kg⁻¹) Max. efficacy (%) I₁ 116 100.0 860 81.7 I₂ Not Not 159 71.2determined determined I₄ Not Not 15 100 determined determined

In the mice hot plate test, analgesic dose-response curves of compoundof compound I₁ was familiar with that of buprenorphine, Max. efficacy ofwhich was less than 100%, which produced a dose-dependent partialagonist properties. Efficacy of compound of compound I₁ was strongerthan that of buprenorphine, especially in serious analgesic models.

In the mice acetic acid writhing test, the Max. analgesic efficacy ofcompound I₁ reached 100% while that of buprenorphine was 92.5%. In thehot plate test, the Max. analgesic efficacy of compound I₁ was 81.7%while that of buprenorphine was 40.3%(Tab 1). In rat 55° C. hot waterbath test and rat formaldehyde test, efficacy and potency of compound I₁was stronger than that of buprenorphine (Tab 0.2). In the rhesus monkeytail flick test, the latency of tail flick was prolonged along withincreasing of dose when given compound I₁ 16-μg·kg⁻¹ im or 6-24 μg·kg⁻¹po, but the effects of the latter was weaker than that of former (Tab4). From above results, compound I₁ showed preferable antinociceptiveactivity. TABLE 2 Antinociceptive activity of compounds writhing testhot plate test ED₅₀ Max. ED₅₀ Compounds (μg · kg⁻¹) efficacy (%) (μg ·kg⁻¹) Max. efficacy (%) I₅ 6.39 100.0 200 71.2 I₆ 55.9 100 50 54.2 I₇Not Not 159.1 94 determined determined Bup 7.3 90 1100 40

In the mice hot plate test, efficacy and potency of compound I₅—I₇ wasstronger than that of buprenorphine, Max. analgesic efficacy of whichwere less than 100%, producing a dose-dependent partial agonistproperties. TABLE 3 Comparison of Antinociceptive effects of compoundsI₁ and buprenorphine in rats formaldehyde test hot water bath test Max.ED₅₀ Max. ED₅₀ efficacy P Compounds (mg · kg⁻¹) efficacy (%) (mg · kg⁻¹)(%) buprenorphine 8.75 64.7 0.34 97.7 I₁ 3.48 79.3 0.15 100.0

TABLE 4 Analgesic effect of compound I₁ in the rhesus monkey tail flicktest Pathway Latency tail Dose of ad- flick Dose Pathway of latency μg ·kg⁻¹ ministration (X ± SD, sec) μg · kg⁻¹ administration (X ± SD, sec) 0Im 3.5 ± 0.2 0 po 4.0 ± 0.7 1 Im 4.8 ± 2.1 6 po 5.1 ± 1.8 2 Im 6.5 ± 3.612 po 6.0 ± 1.9 4 Im  7.9 ± 2.5* 24 po  6.7 ± 2.3* 6 Im  9.2 ± 3.1* 48po  5.7 ± 0.5**P < 0.05, Comparison with 0 μg · kg⁻¹ group; n = 5

In mice hot plate test, analgesic effects of the compound I₁administerted by po and sc, was compared (see FIG. 1). The ED₅₀ value powas 2.5 times of that of sc, but the Max. efficacy of them was almostidentical. In the same test, the ED₅₀ value of buprenorphine po was 12.4times of that of sc. In other analgesic models, the ratio of ED₅₀ valuepo/ED₅₀ value sc of compound I₁ was less than that of buprenorphine (Tab4). The above results indicated that bioavailability of compound I₁ washigher than that of buprenorphine, the range of effective dose ofcompound I₁ was l-3 mg·kg⁻¹ in two analgesic models.

2. Physical Dependent Test

2.1. Methods and Animals

Male Swiss mice, weighing 18-22 g, pretreated with morphine (24 mg·kg⁻¹,s.c.) or buprenorphine (3.6 mg·kg⁻¹, s.c.) or compound I₁ (5.0 mg·kg⁻¹,s.c.) respectively 3 times daily for 14 d, naloxone(10 mg·kg⁻¹, i.p.)was injected 4 h after the last administration of drugs, The number ofjumping was immediately observed within a period of 15 min and loss ofbody weight were marked 60 min after administration of naloxone.

Wister rats, male, weighing 180-200 g, were used. Morphine,buprenorphine and compound I₁ were administrated as mentioned above. 4 hafter the last administration of drugs, all subjects were injectednaloxone(5 mg·kg⁻¹ s.c.). The frequency of gasps, ptosis, shakes, teethchatter and yawns was immediately observed for 15 min after injection ofnaloxone. The total score for abstinence signs was calculated as the sumof the scores for all individual signs of the withdrawal reaction. Lossof body weight was recorded for 60 min after injection of naloxone.

2.2. Results

There was a significant increase in the number of total abstinence signsin morphine-treated group (30×Tid×7d, 30×Tid×14d) compared with salinegroup Statistical evaluation of these data showed no significantdifferences in the number of abstinence syndrome in compound I₁-treatedmice compared with saline group. These data indicated that compound I₁has low potency of dependence. TABLE 5 comparison of the analgesiceffect of compound by s.c. and p.o. administration in mice. ED₅₀ (mg/kg)Methods of test Compound S.C P.O P.O/S.C Acetic Writhing Buprenorphine0.02 0.37 17.6 I₁ 0.08 0.64 8.2 Hot plate Buprenorphine 1.01 12.52 12.4I₁ 0.57 3.10 5.4 tail-flick Buprenorphine 8.75 —* Not detectable I₁ 1.752.61 1.5*<30%

TABLE 6 comparison of the experimental results on the physicaldependence in mice Number of Dose Percent of jumping loss weightCompound (mg · kg⁻¹) (%) jumping (g) Saline — 20  2.1 ± 3.0   0.4 ±0.4   Morphine 24.0 × Tid × 100 49.5 ± 56.0** 1.6 ± 0.2** 14dBuprenorphine 3.6 × Tid × 80 14.6 ± 27.4*  0.8 ± 0.2   14d I₁ 5.0 × Tid× 0   0 ± 0    0.5 ± 0.2   14d2. Psychological Dependence Experiment(1) Conditioned Place Preference Testing in Mice

Swiss mice, male, weighted 18-22 g. Animals were immediately confinedfor 40 min to one compartment after injection of compound I₁, and to theother compartment after injection of saline. Animals that had beeninjected with drugs were confined to one of the end compartments A.M,and to the other of the end compartments after the injection of salineP.M. This tendentious conditioning cycle was performed for 5 d. On day6, preference state, after placing the animals in the neutral middlecompartment and allowing them free access to each compartment. The timespent in drug-paired compartment was measured.

The results are shown in Table 7. As seen in Table 7, morphine (10mg·kg⁻¹) and buprenorphine (0.3 mg·kg⁻¹) and compound I₁ (3 and 10mg·kg⁻¹) induced significant Conditioned Place Preference. TABLE 7comparison of the experimental results on the physical dependence inrats Dose Score of withdrawal loss weight Compound (mg · kg⁻¹)symptoms(%) (g) Saline — 1.8 ± 1.3  1.4 ± 0.6  Morphine 30 × Tid × 7d8.0 ± 2.2** 12.0 ± 2.6** Buprenorphine  5 × Tid × 7d 4.0 ± 2.0  4.2 ±2.5  I₁  3 × Tid × 7d 2.2 ± 1.3  0.4 ± 0.6  Saline — 1.8 ± 1.3  2.8 ±1.3  Morphine 30 × Tid × 14d 6.4 ± 2.2** 4.2 ± 1.2  Buprenorphine  5 ×Tid × 14d 3.6 ± 1.1  4.2 ± 1.3  I₁  3 × Tid × 14d 2.8 ± 0.8  2.0 ± 1.9 

TABLE 8 Experimental results of conditional place preferencein mice DoseTime spent in drug- Compound (mg/kg) paired place (min) Saline — 316.2 ±119.6  Morphine 10 566.6 ± 131.1** Buprenorphine 0.3 547.5 ± 175.0** I₁1 415.3 ± 119.2  3 452.3 ± 66.6*  10 474.0 ± 136.4* (2) Self-administration testing

The subjects were male Wistar rats, 350-400 g and rhesus monkey, 4-6 kgat the start of the experiments. Anesthesia was induced byadministration of sodium pentobarbital (40 mg·kg⁻¹, i.p). Whileanesthetized, rats were implanted with guide cannulas, one end of guidecannulas was implanted right atrium, and the other end was connectedwith self-administration installation. Penicillin Gi was administeredimmediately after surgery.

Self-administration sessions were began 3 days after surgery. Rats weretrained to self-administration compound I₁ at a dose of 0.1 mg·kg⁻¹infusion on FR1 schedule. Daily sessions were 6 h. In duration, thenumber of infusions was recorded, while animals were deprived food.

The results indicated that compound I₁ (0.05, 0.08, 0.1 mg·kg⁻¹)couldn't induce self-administration in rat in continuous 35-40 dayssession (daily injections<10). Opiate receptor partial agonistbuprenorphine also couldn't induce self-administration. Compound I₁(0.025-0.05 mg·kg⁻¹/inject) couldn't induce the development ofself-administration in rhesus monkey. These data indicate that thepotency of dependence of compound I₁ is weak.

3. Substitution Test

(1) Methods and Animals

Methods and animals were as similar to self-administration test. Heroinwas substituted by compound I₁ after development of stableself-administration induced by heroin in rat. Step number and rating wasrecorded.

Stable self-administration was developed by morphine (0.25mg·kg⁻¹/inject) in rhesus monkey. Compound I₁ (0.025 mg·kg⁻¹/inject),morphine (0.25 mg·kg⁻¹ mg·kg⁻¹/inject), buprenorphine (0.05mg·kg⁻¹/inject), morphine (0.25 mg·kg⁻¹/inject) and compound I₁ (0.05mg·kg⁻¹/inject) was substituted by turns.

(2) Results

Self-administration could continue induced by compound I₁ in heroindependent rat. There were not increases of step number of 3 rats, butincreased in other 3 rats. Step numbers were decreased in most of ratcompared with the treatment of heroin.

Compound I, (0.025 mg·kg⁻¹/inject) could continue self-administration inthe place of morphine (0.25 mg/kg/inject), so did buprenorphine.Compound I₁ (0.05 mg·kg⁻¹/inject) could not maintain this test inreplace of morphine (0.25 mg·kg⁻¹/inject) or buprenorphine (0.05mg·kg⁻¹/inject). Results inferred that compound I₁ had potency ofaddict, was as similar as buprenorphine, and was weaker than morphine.

4. Na⁺ Index Determination

(1) Methods

The subjects were male wistar rats, weighing 180-200 g. Rats weresacrificed by decapitation. The brain of rats without cerebellum wasused to make membrane preparation containing opiate receptors, The brainwas homogenized in 50 mmol·L⁻¹ tris-HCL solutions and centrifuged(20,000 rev/min, 20 min). This procedure was repeated twice more. Eachassay contained 0.5 mg membrane protein, 5 nmol·L⁻¹ ³H-naloxone anddifferent concentrations of drugs (1-1100000 nmol·L⁻¹). Nonspecificbinding was determined in the presence of 10 μmol·L⁻¹ naloxone. The IC₅₀was calculated with Logit method. The Na⁺ index was determined by theratio of the IC₅₀ in the presence of 100 nmol·L⁻¹ NaCl to those inabsence of it,

(2) Results

Compound I₁ could inhibit ³H-naloxone binding with opiate receptors assimilar to morphine and buprenorphine. The affinity of formula It toopiate receptors was higher 100 times than that of morphine. Na⁺ indexis 0.42, which is character of typical antagonist. TABLE 9 Influence ofNa⁺ in competitive inhibition of drugs on binding affinity with opiatereceptors of rat brain IC₅₀ (nmol · L⁻¹) Na⁺ Compound Free of Na⁺Presence of Na⁺ index Morphine 18 170 9.44 Buprenorphine 0.45 0.30 0.67I₁ 0.19 0.08 0.42

In all, we have described this invention in detail by using preferredembodiments of the invention. Obviously, it is allowed to improve andtransform the invention at the premise of undeviating from privilege ofthe invention.

1. An oripavine derivative represented by formula (1),

wherein R¹ is hydrogen or methyl, R² is methyl, cyclopropyl methyl,cyclobutyl methyl or allyl, R³ is thiophenyl ethyl or cycloalkyl methylwhere the cycloalkyl has 3 to 6 carbon atoms, or a non-toxicpharmaceutically acceptable salt thereof.
 2. The oripavine derivative ornon-toxic pharmaceutically acceptable salt thereof according to claim 1,characterized in that R³ is thiophenyl ethyl.
 3. The oripavinederivative or non-toxic pharmaceutically acceptable salt thereofaccording to claim 1, characterized in that R² is cyclopropyl methyl, R³is cycloalkyl methyl where the cycloalkyl has 3 to 6 carbon atoms. 4.The oripavine derivative or non-toxic pharmaceutically acceptable saltthereof according to claim 2, characterized in that the compound isrepresented by the following formula:


5. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 2, characterized in that the compound isrepresented by the following formula:


6. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 2, characterized in that the compound isrepresented by the following formula:


7. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 2, characterized in that the compound isrepresented by the following formula:


8. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 3, characterized in that the compound isrepresented by the following formula:


9. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 3, characterized in that the compound isrepresented by the following formula:


10. The oripavine derivative or non-toxic pharmaceutically acceptablesalt thereof according to claim 3, characterized in that the compound isrepresented by the following formula:


11. A pharmaceutical composition comprising as active ingredientoripavine derivative or no-toxic pharmaceutically acceptable saltthereof according to any one of claims 1 to 10 and pharmaceuticalacceptable carriers.
 12. Use of oripavine derivative or non-toxicpharmaceutically acceptable salt thereof according to any one of claims1 to 10 for the preparation of analgesics or abstinence agents of opiumhabit-forming drugs.